It is well-established that long-latency event-related brain potentials are elicited in both humans and experimental animals. These slow potentials are altered in a variety of psychiatric disorders and in the elderly. It has been suggested that such potentials reflect fundamental functional processes that are operational across several species. Indirect evidence suggests that these event-related slow potentials (ERSPs) reflect the activity of neuronal systems which mediate their effects via "neurotransmitter" substances such as norepinephrine, dopamine, 5-hydroxytryptamine or acetylcholine. The long-term objective is to understand brain mechanisms of ERSP generation; the objective of this project is to determine whether or not cortical ERSPs are regulated by certain transmitters acting with the cortex. The principal approach involves determination of the effects on ERSPs of neurotoxin-induced lesions of transmitter input to the neocortex. ERSP effects of drugs which modify the activity of neuromodulator systems will also be examined. Neurophysiological recordings will be obtained in chronically-prepared, freely moving rats responding to an auditory cue preceding rewarding stimulation of the medial forebrain bundle. Appropriate stimulus parameters are determined by behavioral techniques (self-stimulation). To evaluate lesion effects, ERSPs will be recorded bilaterally following unilateral lesions of noradrenergic, dopaminergic, 5-hydroxytryptaminergic and cholinergic pathways to the cortex or localized neurotoxin injections. Effectiveness and specificity of the lesions will be ascertained by regional neurochemical analysis of monoamine content and uptake as well as choline acetyltransferase activity. Dose-response data will be obtained for evaluation of drug-induced alterations of the ERSPs.